The long term objective of this proposal is to determine the molecular basis of hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) through the identification and characterization of the gene for this disorder. HNA is an autosomal dominant disorder associated with recurrent episodes of painful brachial plexus dysfunction. Individuals with HNA may suffer repeated episodes of intense pain, paralysis and sensory disturbances in an affected limb. The onset of HNA may be at birth or later in childhood. Usually the prognosis for recovery is favorable, however persons with HNA may have permanent residual neurologic dysfunction following an attack. The biochemical and molecular basis of HNA is unknown. The gene for HNA has been mapped to chromosome 17q24-25 with evidence for genetic homogeneity. Standard methods of human linkage analysis will be used to identify additional HNA pedigrees, carry out linkage studies aimed to refine the location of the HNA gene on chromosome 17q24-25, test candidate genes and if necessary, isolate a gene for HNA through positional cloning methods. Multiple HNA pedigrees will be ascertained to provide at least 100-200 informative matings for linkage analysis and assessment of genetic homogeneity. Genetic and physical methods will be used to narrow the region of the HNA locus to a 1-2 centimorgan interval, search for transcripts as candidate genes and identify mutations leading to HNA. Identification of the HNA gene will permit the assessment of its patterns of tissue distribution and developmental expression in addition to providing insights into the molecular and biochemical abnormalities leading to the HNA phenotype. Moreover, characterization of the HNA gene may have broader pathophysiological and therapeutic implications for more common idiopathic forms of brachial neuropathy.